tbuckley/cabot-search huggingface dataset:
Ectopic expression of cGAS in<i>Salmonella typhimurium</i>enhances STING-mediated IFN-β response in human macrophages and dendritic cells
Authors: Lisette Waanders, Lieve E H van der Donk, Louis S Ates, Janneke Maaskant, John L van Hamme, Eric Eldering, Jaco A C van Bruggen, Joanne M Rietveld, Wilbert Bitter, Teunis B H Geijtenbeek, Coenraad P Kuijl
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP–AMP dinucleotides with phosphodiester linkages 2′–5′ and 3′–5′ (cGAMPs), that are produced by cyclic GMP–AMP synthetase (cGAS). However, delivery of STING pathway agonists to the tumor site is a challenge. Bacterial vaccine strains have the ability to specifically colonize hypoxic tumor tissues and could therefore be modified to overcome this challenge. Combining high STING-mediated IFN-β levels with the immunostimulatory properties of Salmonella typhimurium could have potential to overcome the immune suppressive tumor microenvironment. Methods We have engineered S. typhimurium to produce cGAMP by expression of cGAS. The ability of cGAMP to induce IFN-β and its IFN-stimulating genes was addressed in infection assays of THP-I macrophages and human primary dendritic cells (DCs). Expression of catalytically inactive cGAS is used as a control. DC maturation and cytotoxic T-cell cytokine and cytotoxicity assays were conducted to assess the potential antitumor response in vitro. Finally, by making use of different S. typhimurium type III secretion (T3S) mutants, the mode of cGAMP transport was elucidated. Results Expression of cGAS in S. typhimurium results in a 87-fold stronger IFN-β response in THP-I macrophages. This effect was mediated by cGAMP production and is STING dependent. Interestingly, the needle-like structure of the T3S system was necessary for IFN-β induction in epithelial cells. DC activation included upregulation of maturation markers and induction of type I IFN response. Coculture of challenged DCs with cytotoxic T cells revealed an improved cGAMP-mediated IFN-γ response. In addition, coculture of cytotoxic T cells with challenged DCs led to improved immune-mediated tumor B-cell killing. Conclusion S. typhimurium can be engineered to produce cGAMPs that activate the STING pathway in vitro. Furthermore, they enhanced the cytotoxic T-cell response by improving IFN-γ release and tumor cell killing. Thus, the immune response triggered by S. typhimurium can be enhanced by ectopic cGAS expression. These data show the potential of S. typhimurium –cGAS in vitro and provides rationale for further research in vivo.
Naive T cells inhibit the outgrowth of intractable antigen-activated memory T cells: implications for T-cell immunotherapy
Authors: Sandhya Sharma, Mae Woods, Naren U Mehta, Tim Sauer, Kathan S Parikh, Michael Schmueck-Henneresse, Huimin Zhang, Birju Mehta, Malcolm K Brenner, Helen E Heslop, Cliona M Rooney
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific T cells from patients. Here, we examine reasons for and solutions to this failure, taking as our model the preparation of Epstein-Barr virus (EBV)-specific T cells (EBVSTs) for the treatment of EBV-positive lymphoma. EBVSTs could not be manufactured from almost one-third of patients, either because they failed to expand, or they expanded, but lacked EBV specificity. We identified an underlying cause of this problem and established a clinically feasible approach to overcome it. Methods CD45RO+CD45RA− memory compartment residing antigen-specific T cells were enriched by depleting CD45RA positive (+) peripheral blood mononuclear cells (PBMCs) that include naïve T cells, among other subsets, prior to EBV antigen stimulation. We then compared the phenotype, specificity, function and T-cell receptor (TCR) Vβ repertoire of EBVSTs expanded from unfractionated whole (W)-PBMCs and CD45RA-depleted (RAD)-PBMCs on day 16. To identify the CD45RA component that inhibited EBVST outgrowth, isolated CD45RA+ subsets were added back to RAD-PBMCs followed by expansion and characterization. The in vivo potency of W-EBVSTs and RAD-EBVSTs was compared in a murine xenograft model of autologous EBV+ lymphoma. Results Depletion of CD45RA+ PBMCs before antigen stimulation increased EBVST expansion, antigen-specificity and potency in vitro and in vivo. TCR sequencing revealed a selective outgrowth in RAD-EBVSTs of clonotypes that expanded poorly in W-EBVSTs. Inhibition of antigen-stimulated T cells by CD45RA+ PBMCs could be reproduced only by the naïve T-cell fraction, while CD45RA+ regulatory T cells, natural killer cells, stem cell memory and effector memory subsets lacked inhibitory activity. Crucially, CD45RA depletion of PBMCs from patients with lymphoma enabled the outgrowth of EBVSTs that failed to expand from W-PBMCs. This enhanced specificity extended to T cells specific for other viruses. Conclusion Our findings suggest that naïve T cells inhibit the outgrowth of antigen-stimulated memory T cells, highlighting the profound effects of intra-T-cell subset interactions. Having overcome our inability to generate EBVSTs from many patients with lymphoma, we have introduced CD45RA depletion into three clinical trials: NCT01555892 and NCT04288726 using autologous and allogeneic EBVSTs to treat lymphoma and NCT04013802 using multivirus-specific T cells to treat viral infections after hematopoietic stem cell transplantation.
Cerebral Small Vessel Disease Progression and the Risk of Dementia: A 14-Year Follow-Up Study
Authors: Mina A. Jacob, Mengfei Cai, Vera van de Donk, Mayra Bergkamp, José Marques, David G. Norris, Roy P.C. Kessels, Jurgen A.H.R. Claassen, Marco Duering, Anil M. Tuladhar, Frank-Erik de Leeuw
Journal: American Journal of Psychiatry (2023)

Cerebral small vessel disease (SVD) is considered the most important vascular contributor to cognitive decline and dementia, although a causal relation between its MRI markers and dementia still needs to be established. The authors investigated the relation between baseline SVD severity as well as SVD progression on MRI markers and incident dementia, by subtype, in individuals with sporadic SVD over a follow-up period of 14 years.The study included 503 participants with sporadic SVD, and without dementia, from the prospective Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, with screening for baseline inclusion conducted in 2006. Follow-ups in 2011, 2015, and 2020 included cognitive assessments and MRI scans. Dementia was diagnosed according to DSM-5 criteria and stratified into Alzheimer's dementia and vascular dementia.Dementia as an endpoint was available for 498 participants (99.0%) and occurred in 108 participants (21.5%) (Alzheimer's dementia, N=38; vascular dementia, N=34; mixed-etiology Alzheimer's dementia/vascular dementia, N=26), with a median follow-up time of 13.2 years (interquartile range, 8.8-13.8). Higher baseline white matter hyperintensity (WMH) volume (hazard ratio=1.31 per 1-SD increase, 95% CI=1.02-1.67), presence of diffusion-weighted-imaging-positive lesions (hazard ratio=2.03, 95% CI=1.01-4.04), and higher peak width of skeletonized mean diffusivity (hazard ratio=1.24 per 1-SD increase, 95% CI=1.02-1.51) were independently associated with all-cause dementia and vascular dementia. WMH progression predicted incident all-cause dementia (hazard ratio=1.76 per 1-SD increase, 95% CI=1.18-2.63).Both baseline SVD severity and SVD progression were independently associated with an increase in risk of all-cause dementia over a follow-up of 14 years. The results suggest that SVD progression precedes dementia and may causally contribute to its development. Slowing SVD progression may delay dementia onset.
Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial
Authors: Sikander Ailawadhi, Zi Chen, Bo Huang, Aneel Paulus, Mary C. Collins, Lei (Tommy) Fu, Mingyu Li, Mohammad Ahmad, Lichuang Men, Hengbang Wang, Matthew S. Davids, Eric Liang, Divya J. Mekala, Zhicong He, Masa Lasica, Costas K. Yannakou, Ricardo Parrondo, Laura Glass, Dajun Yang, Asher Chanan-Khan, Yifan Zhai
Journal: Clinical Cancer Research (2023)

Abstract Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.
Quality of Care and Clinical Outcomes for Patients With Heart Failure at Hospitals Caring for a High Proportion of Black Adults
Authors: Jamie Diamond, Iyanuoluwa Ayodele, Gregg C. Fonarow, Karen E. Joynt-Maddox, Robert W. Yeh, Gmerice Hammond, Larry A. Allen, Stephen J. Greene, Karen Chiswell, Adam D. DeVore, Clyde Yancy, Rishi K. Wadhera
Journal: JAMA Cardiology (2023)

Black adults with heart failure (HF) disproportionately experience higher population-level mortality than White adults with HF. Whether quality of care for HF differs at hospitals with high proportions of Black patients compared with other hospitals is unknown.
A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory <i>BRAF</i> p.V600E-Mutated Differentiated Thyroid Cancer
Authors: Sophie Leboulleux, Christine Do Cao, Slimane Zerdoud, Marie Attard, Claire Bournaud, Ludovic Lacroix, Danielle Benisvy, David Taïeb, Stéphane Bardet, Marie Terroir-Cassou-Mounat, Nadège Anizan, Emilie Bouvier-Morel, Livia Lamartina, Georges Lion, Sarah Betrian, Christophe Sajous, Aurélie Schiazza, Marie-Eve Garcia, Renaud Ciappuccini, Martin Schlumberger, Abir Al Ghuzlan, Yann Godbert, Isabelle Borget
Journal: Clinical Cancer Research (2023)

Abstract Purpose: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation. Patients and Methods: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion &amp;gt; 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq–150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. Results: Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3–4 AEs in 7 patients. Conclusions: Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.
Long-term treatment outcome of patients with complete bilateral cleft lip and palate: a retrospective cohort study
Authors: Yoshitsugu Hattori, Betty C.-J. Pai, Takafumi Saito, Pang-Yun Chou, Ting-Chen Lu, Chun-Shin Chang, Yu-Ray Chen, Lun-Jou Lo
Journal: International Journal of Surgery (2023)

Background: Patients with cleft lip and palate have functional and esthetic impairment and typically require multiple interventions in their life. Long-term evaluation following a treatment protocol, especially for patients with complete bilateral cleft lip and palate (BCLP), is important but was rarely reported in the literature. Patients and methods: A retrospective review was conducted on all patients with complete BCLP born between 1995 and 2002 and treated at our center. Inclusion criteria were having adequate medical records and receiving continuous multidisciplinary team care at least until 20 years of age. Exclusion criteria were lack of regular follow-up and congenital syndromic abnormalities. The medical records and photos were reviewed, and facial bone development was evaluated using cephalometric analysis. Results: A total of 122 patients were included, with a mean age of 22.1 years at the final evaluation in this study. Primary one-stage cheiloplasty was performed in 91.0% of the patients, and 9.0% underwent two-stage repair with an initial adhesion cheiloplasty. All patients underwent two-flap palatoplasty at an average of 12.3 months. Surgical intervention for velopharyngeal insufficiency was required in 59.0% of patients. Revisional lip/nose surgery was performed in 31.1% during growing age and in 64.8% after skeletal maturity. Orthognathic surgery was applied in 60.7% of patients with retruded midface, of which 97.3% underwent two-jaw surgery. The average number of operations to complete the treatment was 5.9 per patient. Conclusion: Patients with complete BCLP remain the most challenging group to treat among the cleft. This review revealed certain suboptimal results, and modifications have been made to the treatment protocol. Longitudinal follow-up and periodic assessment help to establish an ideal therapeutic strategy and improve overall cleft care.
Race and Ethnicity–Adjusted Age Recommendation for Initiating Breast Cancer Screening
Authors: Tianhui Chen, Elham Kharazmi, Mahdi Fallah
Journal: JAMA Network Open (2023)

Importance Breast cancer (BC) is the second leading cause of cancer death in women, and there is a substantial disparity in BC mortality by race, especially for early-onset BC in Black women. Many guidelines recommend starting BC screening from age 50 years; however, the current one-size-fits-all policy to start screening all women from a certain age may not be fair, equitable, or optimal. Objective To provide race and ethnicity–adapted starting ages of BC screening based on data on current racial and ethnic disparities in BC mortality. Design, Setting, and Participants This nationwide population-based cross-sectional study was conducted using data on BC mortality in female patients in the US who died of BC in 2011 to 2020. Exposures Proxy-reported race and ethnicity information was used. The risk-adapted starting age of BC screening by race and ethnicity was measured based on 10-year cumulative risk of BC-specific death. Age-specific 10-year cumulative risk was calculated based on age group–specific mortality data without modeling or adjustment. Main Outcomes and Measures Disease-specific mortality due to invasive BC in female patients. Results There were BC-specific deaths among 415 277 female patients (1880 American Indian or Alaska Native [0.5%], 12 086 Asian or Pacific Islander [2.9%], 62 695 Black [15.1%], 28 747 Hispanic [6.9%], and 309 869 White [74.6%]; 115 214 patients died before age 60 years [27.7%]) of any age in the US in 2011 to 2020. BC mortality per 100 000 person-years for ages 40 to 49 years was 27 deaths in Black females, 15 deaths in White females, and 11 deaths in American Indian or Alaska Native, Hispanic, and Asian or Pacific Islander females. When BC screening was recommended to start at age 50 years for all females with a 10-year cumulative risk of BC death of 0.329%, Black females reached this risk threshold level 8 years earlier, at age 42 years, whereas White females reached it at age 51 years, American Indian or Alaska Native and Hispanic females at age 57 years, and Asian or Pacific Islander females 11 years later, at age 61 years. Race and ethnicity–adapted starting ages for Black females were 6 years earlier for mass screening at age 40 years and 7 years earlier for mass screening at age 45 years. Conclusions and Relevance This study provides evidence-based race-adapted starting ages for BC screening. These findings suggest that health policy makers may consider a risk-adapted approach to BC screening in which individuals who are at high risk are screened earlier to address mortality due to early-onset BC before the recommended age of mass screening.
Assessment of Accuracy, User Engagement, and Themes of Eating Disorder Content in Social Media Short Videos
Authors: Valerie Lookingbill, Ehsan Mohammadi, Yizhou Cai
Journal: JAMA Network Open (2023)

Social media is simultaneously home to communities of users who promote eating disorders as a lifestyle and users who advocate for recovery. As studies have confirmed an association between exposure to pro-eating disorder content and engaging in disordered eating behaviors, an examination of the accuracy of and interactions with information shared in these complex and contradictory communities can provide insights into content available to users at risk.To determine the associations among themes, accuracy of information, and user engagement of eating disorder content on a short video-sharing social media platform.This qualitative study included a thematic analysis of a sample of 200 TikTok videos, as well as user engagement metrics and content creator characteristics, between February and June 2022. Data were analyzed from March to June 2022.Content themes, accuracy of information, user engagement, and the associations among these factors were identified in a sample of eating disorder videos on a social media platform. Data were analyzed with Pearson χ2, analysis of variance, linear regression, and random permutation tests.Among the 200 videos assessed, 124 (62.0%) covered prorecovery content, 59 (29.5%) included pro-eating disorder content, and 17 (8.5%) contained anti-eating disorder content. Thematic analysis revealed 4 high-level themes: (1) encouraging the development or sustainment of eating disorders, (2) sharing physical or emotional experiences with eating disorders, (3) sharing narratives of recovery, and (4) social support. While the results of Pearson χ2 test indicated that videos in the prorecovery domain contained more accurate content than videos categorized in the pro-eating disorder and anti-eating disorder domains (χ24 = 157.92; P < .001), the results of analysis of variance demonstrated that there was no significant difference in user engagement between informative and misleading content (likes: F = 0.110; P = .95; comments: F = 2.031; P = .13; views: F = 0.534; P = .59; shares: F = 0.691; P = .50). Results of the 10 000 random permutation tests, in which all P values were between .40 and .60 regardless of the distances, suggested that there was no significant difference in user engagement among the 3 domains.This mixed-methods qualitative analysis of misleading eating disorder information on social media found that pro-eating disorder and prorecovery communities were prevalent. However, social media users in the prorecovery community created more informative than misleading content. Furthermore, the study found no significant difference between users' engagement with accurate vs misleading videos, which may suggest that false information alone does not influence the virality of videos.
Perceptions of Health Care–Associated Infection Metrics by Infection Control Experts
Authors: Gregory M. Schrank, Westyn Branch-Elliman, Surbhi Leekha, Jonathan Baghdadi, Lisa Pineles, Anthony D. Harris, Daniel J. Morgan
Journal: JAMA Network Open (2023)

This survey study examines the perceptions of US infection control experts on commonly reported measures of health care–associated infections.
The Benefits of Surgery for Diverticular Disease—Have We Met the Burden of Proof?
Authors: Susanna S. Hill, Jennifer S. Davids
Journal: JAMA Surgery (2023)

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